Project Summary The yellow fever mosquito Aedes aegypti is the principal vector of several medically-important arboviruses, such as Zika, chikungunya, and dengue. The control of mosquito-borne diseases relies on the use of insecticides targeting the nervous system of mosquitoes (e.g., pyrethroids) to reduce their populations. However, the emergence of insecticide resistance in mosquitoes has reduced the efficacy of these control agents. Thus, new insecticides targeting novel molecular and physiological targets are needed to embellish our chemical toolbox for vector control. We have recently discovered a drimane sesquiterpene dialdehyde (cinnamodial, CDIAL) from the bark of an endemic plant of Madagascar (Cinnamosma fragrans; family Canellaceae) that is toxic to adult female and larval Ae. aegypti. Moreover, CDIAL is equally toxic to representative pyrethroid-susceptible (Liverpool) and pyrethroid-resistant (Puerto Rico) strains of Ae. aegypti, suggesting a novel mechanism of action from pyrethroids. The goals of the proposed research are to 1) elucidate the structure-toxicity relationship of CDIAL against Ae. aegypti, and 2) develop natural and synthetic analogs of CDIAL with improved efficacy as mosquitocides. Aim 1 will use leading-edge natural product drug discovery, biotransformation, and medicinal chemistry approaches to develop a library of CDIAL analogs. Aim 2 will evaluate the toxicity of the analogs in larval and adult female Ae. aegypti from pyrethroid-susceptible and pyrethroid-resistant strains. Analogs with improved potency compared to CDIAL will be assessed for potential mammalian/human safety using an in vitro cytotoxicity assay with a normal cell line (African green monkey Vero cells). The results from the two aims will yield a diverse collection of natural compounds and their synthetic derivatives that offer high potential for development into safe, resistance-breaking mosquitocides for controlling the primary vector of Zika, dengue, and chikungunya viruses.